AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance
The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor target...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558619302131 |
| _version_ | 1819211148373786624 |
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| author | Wael Jdey Maria Kozlak Sergey Alekseev Sylvain Thierry Pauline Lascaux Pierre-Marie Girard Françoise Bono Marie Dutreix |
| author_facet | Wael Jdey Maria Kozlak Sergey Alekseev Sylvain Thierry Pauline Lascaux Pierre-Marie Girard Françoise Bono Marie Dutreix |
| author_sort | Wael Jdey |
| collection | DOAJ |
| description | The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10−8) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10−7 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment. |
| first_indexed | 2024-12-23T06:22:28Z |
| format | Article |
| id | doaj.art-80e654e249474737a03c15c193628e80 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-23T06:22:28Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-80e654e249474737a03c15c193628e802022-12-21T17:57:09ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862019-09-01219863871AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired ResistanceWael Jdey0Maria Kozlak1Sergey Alekseev2Sylvain Thierry3Pauline Lascaux4Pierre-Marie Girard5Françoise Bono6Marie Dutreix7Institut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, France; Onxeo, F-75015, Paris, FranceInstitut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, FranceInstitut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, FranceInstitut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, FranceOnxeo, F-75015, Paris, FranceInstitut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, FranceOnxeo, F-75015, Paris, FranceInstitut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, France; Address all correspondence to: Marie Dutreix, Institut Curie UMR3347, Université Paris-Sud, Building 112, 15, rue Georges Clémenceau, – F-91405 Orsay, France. Tel.: +33 1 69 86 71 86; fax: +33 1 69 86 31 41.The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10−8) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10−7 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment.http://www.sciencedirect.com/science/article/pii/S1476558619302131 |
| spellingShingle | Wael Jdey Maria Kozlak Sergey Alekseev Sylvain Thierry Pauline Lascaux Pierre-Marie Girard Françoise Bono Marie Dutreix AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance Neoplasia: An International Journal for Oncology Research |
| title | AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance |
| title_full | AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance |
| title_fullStr | AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance |
| title_full_unstemmed | AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance |
| title_short | AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance |
| title_sort | asidna treatment induces cumulative antitumor efficacy with a low probability of acquired resistance |
| url | http://www.sciencedirect.com/science/article/pii/S1476558619302131 |
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